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Helminth-derived proteins as immune system regulators: a systematic review of their promise in alleviating colitis


Helminth-derived proteins have immunomodulatory properties, influencing the host’s immune response as an adaptive strategy for helminth survival. Helminth-derived proteins modulate the immune response by inducing anti-inflammatory cytokines, promoting regulatory T-cell development, and ultimately favouring a Th2-biased immune response. This systematic review focused on helminth-derived proteins and explored their impact on reducing inflammatory responses in mouse models of colitis. A systematic search across Medline, EMBASE, Web of Science, and Cochrane Library identified fourteen relevant studies. These studies reported immunomodulatory changes, including increased production of anti-inflammatory cells and cytokines. In mouse models of colitis treated with on helminth-derived proteins, significant improvements in pathological parameters such as body weight, colon length, and microscopic inflammatory scores were observed compared to control groups. Moreover, helminth-derived proteins can enhance the function of Tregs and alleviate the severity of inflammatory conditions. The findings underscore the pivotal role of helminth-derived proteins in immunomodulation, specifically in the axis of cytokine secretion and immune cell polarization. The findings offer new opportunities for treating chronic inflammatory conditions such Crohn’s disease.

Peer Review reports


Helminthes infections pose a significant global public health challenge, with recent estimations indicating that approximately 1.5 billion individuals are affected by one or more prevalent helminth infections. The majority of affected individuals reside in low- and middle-income countries located in endemic regions such as Asia, Latin America, the Caribbean, and sub-Saharan Africa [1]. These helminthes show notable variations in their biological life cycles and distinct variation in tissue tropism. The observed variations in clinical outcomes among helminth parasites can be attributed to these differences. The adverse outcomes of helminth infection are commonly linked to two factors: the level of parasite presence (also known as intensity or burden) and the duration of the infection, whether it is acute or chronic. Parasitic infection burden in humans have been linked to genetic phenotypes [1]. An initial genomic analysis of helminthes infection discovered a significant correlation between the intensity of parasitic infection and specific genetic markers encoding Th2 cytokines. The ongoing research effort in the field is exploring the host genes that have an impact on helminthes infection mostly focuses on schistosomiasis [2].

The duration of infection is a second contributing factor to the adverse outcome of helminthes infection. Numerous helminthiases are characterized by their chronic nature, and the mechanisms underlying the regulation of the Th2 immune response during the prolonged duration of these infections remains unclear, wherein antigen levels stay elevated and immunological-mediated pathology persists [3] There is a significant attention directed on the potential involvement of regulatory T cells (Tregs) in these physiological mechanisms,

potentially in conjunction with immunoregulatory molecules derived from helminths [4].

Recent studies have highlighted the significance of understanding the various mechanisms that parasites employ to modulate the immune response in favor of their survival within the host [5, 6]. . A review by Maizels et al. 2016 has indicated that the presence of live stages of the parasites in the host body can result in immunosuppression, but treating these parasites can restore the immune response of the host [5]. Furthermore, extracellular vesicles, proteins, or metabolites released or expelled by the parasite may also directly activate signaling pathways in host cells. Thus, scientists and researchers are investigating the proteins and components released by these parasites, as well as their role in overriding the host’s immune system [7]. Over time, humans have developed a balance between various immune responses due to childhood exposure to pathogens. The Th1/Th17 response is directed towards bacterial infections and autoimmunity, while the Th2 response is geared towards allergies and parasites. Parasitic infections can inhibit autoimmunity by promoting the Th2 response and inhibiting the Th1 response [8]. Research suggests that specific parasites may prevent allergic diseases and autoimmune disorders like multiple sclerosis, type 1 diabetes mellitus, and inflammatory bowel disease (IBD) [9].

IBD most often affects young adults, with symptoms ranging from abdominal pain, diarrhea, and bloody stool due to undetermined intestinal inflammation. There are two main types of IBD: Ulcerative Colitis (UC) and Crohn’s Disease (CD) [10]. These conditions affect the lining of the colon and the entire digestive tract, but the exact cause of IBD is still unknown. It is believed that an abnormal immune response to the bacteria in the gut may be responsible for the development of UC and CD [10]. Researchers have used various mouse models to study IBD and understand the mechanisms of chronic inflammation in the intestine. Chemicals such as Dextran Sodium Sulfate (DSS), Trinitrobenzene Sulfonic Acid (TNBS), and Dinitrobenzene Sulfonic Acid (DNBS) can be used to induce colitis, as well as spontaneous mutations, adoptive T-cell transfer, microbiome induction, and genetic engineering methods like IL-10 knockout mice [8, 11,12,13,14].

The management of inflammation is frequently achieved through the use anti-inflammatory medications, including corticosteroids, aminosalicylates, immunosuppressors, and anti-tumor necrosis factor (anti-TNF) agents. Surgical treatments are commonly advised as a treatment approach for cases of intestinal stenosis and fistula [8]. .Nevertheless, inflammatory bowel disease (IBD) is characterized by its resistance to treatment and the absence of a complete cure.

Given the immune-regulating properties of helminth infections, clinical trials have shown promising data using the helminth species Trichuris suis and Necator americanus in treating several inflammatory and autoimmune diseases [15]. Though, phase 2 trials of Trichuris suis failed to reach their clinical endpoints in IBD and multiple sclerosis as the effects of its treatment were modest in magnitude and varied greatly between study subjects. Furthermore, human helminth treatment should not be undertaken outside of controlled clinical trials [16,17,18]. The exploration and development of new medicinal substances derived from helminths are of paramount importance, given their well-documented anti-inflammatory properties. Our research efforts were focused on investigating the efficacy of helminth-derived proteins (HDPs) in animal (mouse) models of colitis.


Search strategy and study selection

The systematic review of Observational Studies in Epidemiology (MOOSE) guidelines [19]. It was also reported following the Preferred Reporting Items for Systematic Reviews (PRISMA) statement [20].

To identify relevant studies, an extensive search approach was designed, as shown in Fig. 1. From inception until December 2022, a thorough electronic search of bibliographic databases such as Medline, Embase, and Cochrane Library was conducted. With English and American spellings, keywords, Emtree, and MeSH terms were employed. The following keywords were used in the search strategy: (“inflammatory bowel disease” OR “IBD” OR “Ulcerative colitis” OR “Crohn’s disease”) and (“parasites” OR “helminths” OR “worms” OR “parasite secretory products” OR “parasite products” OR “parasite-derived proteins”).

Fig. 1
figure 1

PRISMA Flow Diagram for Study Inclusion and Exclusion Process Using Multiple Databases. The databases used are Medline, EMBASE, Web of Science, and Cochrane Library databases. *Title and abstract screening are conducted to examine records. n = number of studies

Inclusion and exclusion criteria

We gathered studies investigating helminths’ immunomodulatory effects on colitis mouse models. We excluded conference proceedings, reviews, studies not published in English, in vitro studies, and clinical trials. Additionally, we excluded studies that utilized parasite infection or excretory-secretory (ES) methods for analysis.

Initially, AN and HA perform the search strategy for possible keywords that belong to the aim of this project. Then, the selected papers were screened by MA, AZ, TT, and FM, each study’s title and abstract evaluated independently to see if it meets the inclusion/exclusion criteria. As a result, all of the researchers (MA, AZ, TT, and FM) independently conducted a two-step full-text literature search to assess eligibility further.

Data extraction and data synthesis

All researchers performed data extraction from the relevant studies independently using a standardized data collection form for all included studies. Each study retrieved the following demographic information: study description, data source, and type of helminths, type of colitis models, type of intervention, and compared groups. Moreover, the outcomes (cellular polarization, cytokines profile and pathological changes) were extracted from each study.

We categorized the helminths according to the external and internal morphology of egg, larval, and adult stages to trematodes, nematodes, filarial nematodes, and cestodes. Moreover, our data summarized the different IBD mouse models used by reported studies to induce colitis chemically (DSS, TNBS, or DNBS) and adoptive T Cell Transfer. In addition, Finally, we extracted the cellular and cytokines and pathological changes from each study to investigate the intervention changes compared to the control group. To assess the quality of included studies, we used the Systematic Review Center for Laboratory Animal Experimentation (the SYRCLE risk of bias tool) [21].


Characteristics of included studies

From the original search we retrieved 1441 studies, of these, a total of 14 studies were thoroughly analysed as they met strict inclusion criteria (Fig. 1), focusing on proteins derived from helminths. The selected studies were conducted between the year of 2002 to the year of 2022. Our examination revealed that Schistosoma and Trichinella were the most extensively studied helminths, with six and four studies, respectively. Two studies were conducted on hookworms (Necator americanus and Ancylostoma caninum) and filarial nematodes (Brugia malayi and Wuchereria bancrofti). Additionally, one study was conducted on Ascaris and Clonorchis.

Among the Colitis-mouse studies, the TNBS-induced colitis model was the most frequently used, with eleven studies. Six studies employed the DSS-induced colitis model, while one utilized Adoptive T-cell transfer. Most studies compared the effect of each intervention to PBS, with only three studies adopting a different approach, as shown in Table 1.

Table 1 The demographic data of all the studies included in this systematic review

Quality of included studies

Based on a comprehensive analysis of animal studies using the SYRCLE risk of bias tool, we have identified specific categories that display a higher to intermediate risk of bias, including randomization, performance, detection, and attribution. However, we have also come across categories indicating a low risk of bias, such as selection, reporting, and potential biases. Please refer to Fig. 2 and Table S1 for a more detailed understanding.

Fig. 2
figure 2

Risk-of-bias assessment graph, using the SYRCLE tool: review authors’ judgments for each domain; Selection, Performance, Detection, Attrition, Reporting, and Other Bias presented as percentages across the included studies

The immunoregulatory effect of recombinant proteins derived from helminths

Polarization of immune cells is a common feature of the host response to microbial infection, inflammation, fibrosis, and tissue repair. Different studies illustrated the ability of parasites to modify hosts’ immune systems and contribute to the polarization of their immune response. We have found that several studies suggest that helminths could positively impact the immune system by increasing the number of regulatory T cells (Table 2). Although these studies used different approaches to investigate the effects of various helminths on colitis, they have shown that proteins from various helminths can boost Treg cell expansion in critical areas of the body, including the mLN, Lamina propria, Spleen, and colon.

Table 2 The effect of helminth-drive protein intervention on T regulatory cell polarization in the IBD-mouse model compared to the control group

When proteins from helminths are administered to mice with induced colitis, it reduces the production of Th1/Th17 cytokines, such as IL-1β, IL-6, TNF-α, IL-17, and IFN-γ, while increasing the production of Th2/Treg cytokines, such as IL-4, IL-13, TGFβ, and IL-10 in the serum, colon homogenates, and spleen (< Emphasis Type="Bold”> Table 3</Emphasis> ). After analyzing the colon homogenates cytokine profile following the treatment with helminths-derived renominate protein, there was a significant decrease in IL-1β, IL-6, TNF-α, IL-17, and IFN-γ levels and an increase in the levels of IL-4, IL-13, TGFβ, and IL-10. However, a study revealed that treatment with Trichinella spiralis-derived recombinant protein leads to a rise in TNF-α and IFN-γ in serum.

Regarding serum, most studies showed similar cytokine profiling after treatment with helminths-derived renominate protein to colon homogenates. However, one study demonstrated an increase in pro-inflammatory cytokines. Finally, cytokine changes from mesenteric lymph nodes (mLN) and spleen showed a similar pattern.

Table 3 The effect of helminth-drive protein intervention on cytokine changes in the IBD-mouse model compared to control group

Macroscopic/microscopic inflammatory score and disease activity index score

Based on the findings presented in Table 4, recombinant proteins sourced from helminths have demonstrated efficacy in reducing inflammation in mice with colitis. This mode of treatment has correspondingly yielded improvements in colon length and body weight while reducing both DAI and microscopic inflammatory scores. Furthermore, these studies have shown decreased myeloperoxidase activity (MPO).

Table 4 The effect of helminth-drive protein intervention on pathological changes in the IBD-mouse model compared to the control group


Exploring how parasites adapt to their host environments can have significant therapeutic implications in treating immune-mediated diseases. Research into helminth parasites and their bioproducts can reduce inflammation associated with inflammatory bowel disease (IBD).

Several studies exploited the effects of helminth-derived proteins and peptides on different autoimmune and inflammatory disorders, and most of them showed the ability of these components to regulate the immune response and improve the pathology of these disorders. Moreover, some of these proteins and peptides were studied in vaccine development and showed promising results. However, to our knowledge, all these studies were in the preclinical phase and yet not in clinical trials [36].

Our primary objective is to assess the effectiveness of HDPs with colitis-induced models. Our findings suggest that HDPs derived from intestinal nematodes, filarial nematodes and trematodes, have the potential to modulate the immune response in these models. This regulation is accomplished by activating regulatory T cells, utilizing regulatory cytokines such as IL-10, and enhancing the Th2 immune response while diminishing the Th1 response. It has been previously shown that Tregs can play an important role in regulating immune responses and maintaining homeostasis in several diseases including autoimmune and inflammatory diseases either through cell-cell contact or through the production of immunosuppressive cytokines eg, IL-10 and TGF- β. For instance, type 1 Tregs cells are known to secrete high levels of IL-10, whereas type 3 Tregs cells are recognized for their TGF-β secretion [15]. HDPs are believed to modulate the host’s immune response in favour of the parasite. Immune manipulation mechanisms by HDPs are many some examples includes engaging immune cell receptors, breaking down molecules, disrupting cell-cell signals, and mimicking cytokines (Fig. 3). A remarkable example of how HDPs modulate the host immune response is observing the outcome of the inoculation of hookworms-derived antigens, which are a complex mixture of over 100 proteins with unknown functions in colitis-induced mouse models resulted in the induction of great levels of T-helper type 2 (Th2-related) cells and regulatory cytokines, including IL-10, IL-4, and TGF-β and a corresponding decrease in the inflammatory cytokines including IL-13, TNF-β, IL-1, IFN-γ, and IL-17a [39,40,41,42]. Moreover, IBD-related symptoms have been improved after hookworm-derived antigens inoculation. Other studies also highlight that selected hookworm-derived products could be used to treat autoimmune disorders without using whole live parasites. For example, the most abundant protein produced by hookworm, anti-inflammatory protein (AIP)-1, promoted the recruitment of Treg cells to the gut and allowed rapid healing of the colon mucosa, which aids in the maintenance of the intestine’s tolerance state [42,43,44]. Hookworms have also been shown to induce a type 2 immune response associated with increased circulatory eosinophils[45].

Fig. 3
figure 3

Helminth-derived proteins (HDPs) manipulate the host’s immune system to favour the parasite by engaging receptors, degrading molecules, interfering with signals, and mimicking host cytokines. (1) Certain components of HDPs can redirect immune responses towards anti-inflammatory and Th2 responses by priming Th2/Treg-inducing DCs. (2) HDPs may manipulate the host’s immune system through intracellular molecule degradation, such as breaking down TLR3, disrupting inflammation pathways, suppressing protein synthesis, and causing Th2 polarization. (3) Certain proteins in helminths can suppress the immune system by interfering with signals, such as interfering with T cell receptors and MHCII. (4) Certain HDPs could mimic cytokines and convert naïve T cells into regulatory T cells. Created with

HDPs exhibit immunoregulatory characteristics. For instance, the tapeworm Echinococcus granulosus inhibits the maturation of DCs, and the differentiation of monocytes, resulting in a shift towards a regulated immune [44]. Interestingly, HDPs can also regulate Toll-like receptors (TLRs) signaling to induce a state of tolerance in DCs which subsequently induces the production of anti-inflammatory cytokines such as IL-10 [45]. IL-10 exerts immunosuppressive effects by directly inhibiting TLR signaling, resulting in the overall suppression of APCs activation, and thus inhibiting MHC class II expression. Several mechanisms have been suggested to explain the reduction of APC function by IL-10, The intracellular pathways targeted by these biomolecules are primarily undefined. TLRs are the most described mechanism of their immunomodulatory effect. Interestingly, HDPs can also regulate TLRs signaling to produce a tolerogenic dendritic cell phenotype that secretes anti-inflammatory cytokines [46].

Schistosoma mansoni and its eggs can both produce bioactive antigens, including lysophosphatidylserine, and lacto-N-fucopentaose III (LNFPIII), which can alleviate inflammatory responses by targeting TLRs [47]. It has been found that simultaneously and non-simultaneously activating TLR by HDPs can activate intracellular signaling pathways. This activation is critical in suppressing a Th1 response and polarizing immune responses towards anti-inflammatory and Th2 responses. Examples include Trichinella spiralis muscle larvae, Schistosoma mansoni, and Ascaris lumbricoides-derived phospholipids. These components induce transient ERK1/2 signaling, priming Th2/Treg-inducing DCs and supporting Th2 polarization by generating an imbalance in TLR2 signaling and strengthening the ERK pathway in human monocyte-derived DCs [48, 49]. It is also worth noting that different stages of nematodes have been demonstrated to inhibit NF-κB translocation and phosphorylation of p38 and ERK1/2 in LPS-treated murine macrophage cell lines [50]. Additionally, HDP from Schistosoma mansoni can enter the endosome and degrade TLR3, disrupting intracellular pathways activated during inflammation [51]. Moreover, the suppression of protein synthesis and subsequent Th2 polarization is attributed to the omega-1 protein obtained from Schistosomes [52].

Helminths, like filarial nematodes, nematodes, and trematodes, contain protease inhibitors such as serine and cystatins in their excretory-secretory products. Macrophages uptake filarial cystatin protease inhibitors, which target ERK1/2 and p38 by stimulating dual specificity phosphatases (DUSPs), negative MAPK signalling and IL-10 expression regulators. This helps to modulate downstream signals, inducing regulatory responses [53]. Ascaris lumbricoides cysteine protease inhibitors regulate the immune system by suppressing MHC-II expression and dendritic cell-mediated antigen presentation while promoting nitric oxide and regulatory cytokines like IL-10 and TGF-β. It also helps regulate macrophages for further immune response benefits [54,55,56,57,58]. During the early stages of T. spiralis infection, the secretion of serine protease inhibitors plays a crucial role in immunosuppression. The serine protease inhibitors directly activate macrophages with an alternatively activated phenotype, which helps the adult worms survive in the intestinal tract [59]. Furthermore, Parasite-derived cystatins, such as CPI2 from B. malayi and onchocystatin from Onchocerca volvulus, directly interfere with antigen presentation. This interference occurs by inhibiting proteases involved in antigen presentation, which prevents T-cell activation at the level of T-cell receptor engagement by MHC complexes. Additionally, these cystatins enhance the production of interleukin-10 (IL-10) by APCs [60].

On the other hand, it has been observed that specific proteins obtained from helminths can efficiently weaken the immune system without the involvement of Pattern Recognition Receptors (PRRs) such as TLR. This can lead to interference with antigen presentation, disturbance in T cell receptor (TCR) signalling and mimicking or inhibiting host cytokines.

Low-dose HPDs may prompt weak TCR signaling, resulting in a Th2 response. This hypothesis is based on a study that established a correlation between antigen dosage, cytokine levels, and Th cell characteristics [61]. Additionally, TGF-β homologs have been found in nematodes and trematodes. This highly potent cytokine has immunoregulatory properties that stimulate the transformation of naïve T cells into regulatory T cells [62].

One of the study’s limitation is its focus on mouse models of colitis, which may not accurately represent human immune responses. Additional research involving human subjects is necessary to validate the therapeutic potential of helminth-derived proteins.

Moreover, investigating the impact of proteins obtained from various sources of helminths and taking into account the complex interactions between host immune systems and different species of helminths should improve the applicability of the results. Future studies may need to explore the effects of intact helminths or their various components for a comprehensive understanding of the immunomodulatory potential of helminths


The impact of HDPs on mice with colitis was investigated. The findings indicate that HDPs can regulate the immune system by augmenting the production of anti-inflammatory cytokines and diminishing pro-inflammatory cytokines locally and systemically. Additionally, HDPs can enhance the function of Tregs and alleviate the severity of inflammatory conditions. Additional investigation is needed in order to achieve a comprehensive understanding of the mechanisms by which HDPs enhance the management of inflammatory bowel disease (IBD) and facilitate the creation of innovative therapies for chronic inflammatory conditions.

Data availability

No datasets were generated or analysed during the current study.



Not detected, ↑ increase, ↓ decrease


(Brugia malayi recombinant cystatin)


(Wuchereria bancrofti larval recombinant protein)


(Schistosoma mansoni soluble worm proteins)


(Schistosome 28-kDa glutathione S-transferase)


(Schistosoma japonicum recombinant cystatin)


(S. japonicum recombinant 16-kDa secreted protein)


(Ancylostoma caninum recombinant protein anti-inflammatory protein-1)


(the mutant recombinant protein AIP-1)


(Necator americanus Netrin domain-containing proteins)


(N.americanus low-MW peptide found in the excretory/secretory proteins)


(Ancylostoma caninum recombinant protein anti-inflammatory protein-1)


(A. caninum low-MW peptides (4 kDa each) found in the excretory/secretory proteins)


(Ascaris lumbricoides recombinant cystatin protease)


(Trichinella spiralis recombinant 53-kDa protein)


(T. spiralis newborn larvae recombinant serine protease)


(T. spiralis Kazal-type serine protease inhibitors recombinant protein )


(T. spiralis adult serine protease inhibitors recombinant protein)


(T. spiralis paramyosin recombinant protein)


(Clonorchis sinensis Type I cystatin recombinant protein)


  1. Quinnell RJ. Genetics of susceptibility to human helminth infection. Int J Parasitol. 2003;33:1219–31.

    Article  CAS  PubMed  Google Scholar 

  2. Marquet S, Abel L, Hillaire D, Dessein H, Kalil J, Feingold J, et al. Genetic localization of a locus controlling the intensity of infection by Schistosoma mansoni on chromosome 5q31–q33. Nat Genet. 1996;14:181–4.

    Article  CAS  PubMed  Google Scholar 

  3. Maizels RM, Balic A, Gomez-Escobar N, Nair M, Taylor MD, Allen JE. Helminth parasites - masters of regulation. Immunol Rev. 2004;201:89–116.

    Article  CAS  PubMed  Google Scholar 


    Article  CAS  PubMed  Google Scholar 

  5. Maizels RM, McSorley HJ. Regulation of the host immune system by helminth parasites. J Allergy Clin Immunol. 2016;138:666–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Weinstock JV. Do we need worms to promote Immune Health? Clin Rev Allergy Immunol. 2015;49:227–31.

    Article  CAS  PubMed  Google Scholar 

  7. Johnston MJG, MacDonald JA, McKay DM. Parasitic helminths: a pharmacopeia of anti-inflammatory molecules. Parasitology. 2009;136:125–47.

    Article  CAS  PubMed  Google Scholar 

  8. Wang M, Wu L, Weng R, Zheng W, Wu Z, Lv Z. Therapeutic potential of helminths in autoimmune diseases: helminth-derived immune-regulators and immune balance. Parasitol Res. 2017;116:2065–74.

    Article  PubMed  Google Scholar 

  9. Wu Z, Wang L, Tang Y, Sun X. Parasite-derived proteins for the treatment of allergies and Autoimmune diseases. Front Microbiol. 2017;8:2164.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573–621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Berg DJ, Zhang J, Weinstock JV, Ismail HF, Earle KA, Alila H, et al. Rapid development of colitis in NSAID-treated IL-10–deficient mice. Gastroenterology. 2002;123:1527–42.

    Article  CAS  PubMed  Google Scholar 

  12. Ostanin DV, Bao J, Koboziev I, Gray L, Robinson-Jackson SA, Kosloski-Davidson M, et al. T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade. Am J Physiology-Gastrointestinal Liver Physiol. 2009;296:G135–46.

    Article  CAS  Google Scholar 

  13. Wang SS, Xie YY, Yang XD, Wang XS, Yan K, Zhong ZR et al. Therapeutic potential of recombinant cystatin from Schistosoma japonicum in TNBS-induced experimental colitis of mice. Parasit Vectors. 2016;9.

  14. Wirtz S, Neufert C, Weigmann B, Neurath MF. Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2007;2:541–6.

    Article  CAS  PubMed  Google Scholar 

  15. Arai T, Lopes F. Potential of human helminth therapy for resolution of inflammatory bowel disease: the future ahead. Exp Parasitol. 2022;232:108189.

    Article  CAS  PubMed  Google Scholar 

  16. Fleming J, Hernandez G, Hartman L, Maksimovic J, Nace S, Lawler B, et al. Safety and efficacy of helminth treatment in relapsing-remitting multiple sclerosis: results of the HINT 2 clinical trial. Mult Scler. 2019;25:81–91.

    Article  CAS  PubMed  Google Scholar 

  17. Voldsgaard A, Bager P, Garde E, Åkeson P, Leffers AM, Madsen CG, et al. Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect. Mult Scler. 2015;21:1723–9.

    Article  CAS  PubMed  Google Scholar 

  18. Schölmerich J, Fellermann K, Seibold FW, Rogler G, Langhorst J, Howaldt S, et al. A Randomised, Double-blind, placebo-controlled trial of Trichuris suis ova in active Crohn’s Disease. J Crohns Colitis. 2017;11:390–9.

    PubMed  Google Scholar 

  19. Stroup DF. Meta-analysis of Observational Studies in EpidemiologyA Proposal for Reporting JAMA. 2000;283:2008.

  20. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339(jul21 1):b2535–2535.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14:43.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Khatri V, Amdare N, Tarnekar A, Goswami K, Reddy MVR. Brugia malayi cystatin therapeutically ameliorates dextran sulfate sodium-induced colitis in mice. J Dig Dis. 2015;16:585–94.

    Article  CAS  PubMed  Google Scholar 

  23. Togre NS, Bhoj PS, Khatri VK, Tarnekar A, Goswami K, Shende MR, et al. SXP-RAL family filarial protein, rWbL2, prevents Development of DSS-Induced Acute Ulcerative Colitis. Indian J Clin Biochem. 2018;33:282–9.

    Article  CAS  PubMed  Google Scholar 

  24. Driss V, El Nady M, Delbeke M, Rousseaux C, Dubuquoy C, Sarazin A, et al. The schistosome glutathione S-transferase P28GST, a unique helminth protein, prevents intestinal inflammation in experimental colitis through a Th2-type response with mucosal eosinophils. Mucosal Immunol. 2016;9:322–35.

    Article  CAS  PubMed  Google Scholar 

  25. Wang L, Xie H, Xu L, Liao Q, Wan S, Yu Z, et al. rSj16 protects against DSS-Induced colitis by inhibiting the PPAR-alpha signaling pathway. Theranostics. 2017;7:3446–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sarazin A, Dendooven A, Delbeke M, Gatault S, Pagny A, Standaert A, et al. Treatment with P28GST, a schistosome-derived enzyme, after acute colitis induction in mice: decrease of intestinal inflammation associated with a down regulation of Th1/Th17 responses. PLoS ONE. 2018;13:e0209681.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ferreira IB, Pickering DA, Troy S, Croese J, Loukas A, Navarro S. Suppression of inflammation and tissue damage by a hookworm recombinant protein in experimental colitis. Clin Transl Immunol. 2017;6.

  28. Buitrago G, Pickering D, Ruscher R, Cobos Caceres C, Jones L, Cooper M, et al. A netrin domain-containing protein secreted by the human hookworm Necator americanus protects against CD4 T cell transfer colitis. Transl Res. 2021;232:88–102.

    Article  CAS  PubMed  Google Scholar 

  29. Smallwood TB, Navarro S, Cristofori-Armstrong B, Watkins TS, Tungatt K, Ryan RYM et al. Synthetic hookworm-derived peptides are potent modulators of primary human immune cell function that protect against experimental colitis in vivo. J Biol Chem. 2021;297.

  30. Coronado S, Barrios L, Zakzuk J, Regino R, Ahumada V, Franco L, et al. A recombinant cystatin from Ascaris lumbricoides attenuates inflammation of DSS-induced colitis. Parasite Immunol. 2017;39:4.

    Article  Google Scholar 

  31. Du L, Tang H, Ma Z, Xu J, Gao W, Chen J, et al. The protective effect of the recombinant 53-kDa protein of Trichinella spiralis on experimental colitis in mice. Dig Dis Sci. 2011;56:2810–7.

    Article  CAS  PubMed  Google Scholar 

  32. Qu Z, Jin X, Wang Y, Yang Y, Yang L, Bai X, et al. Effect of recombinant serine protease from newborn larval stage of Trichinella spiralis on 2,4,6-trinitrobenzene sulfonic acid-induced experimental colitis in mice. Acta Trop. 2020;211:105553.

    Article  CAS  PubMed  Google Scholar 

  33. Xu J, Wu L, Yu P, Liu M, Lu Y. Effect of two recombinant trichinella spiralis serine protease inhibitors on TNBS-induced experimental colitis of mice. Clin Exp Immunol. 2018;194:400–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hao C, Wang W, Zhan B, Wang Z, Huang J, Sun X et al. Trichinella spiralis Paramyosin Induces Colonic Regulatory T Cells to Mitigate Inflammatory Bowel Disease. Front Cell Dev Biol. 2021;9 (no pagination).

  35. Jang SW, Cho MK, Park MK, Kang SA, Na BK, Ahn SC, et al. Parasitic helminth cystatin inhibits DSS-induced intestinal inflammation via IL-10(+)F4/80(+) macrophage recruitment. Korean J Parasitol. 2011;49:245–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fleming JO, Weinstock JV. Clinical trials of helminth therapy in autoimmune diseases: Rationale and findings. Parasite Immunol. 2015;37:277–92.

    Article  CAS  PubMed  Google Scholar 

  37. Heylen M, Ruyssers NE, De Man JG, Timmermans JP, Pelckmans PA, Moreels TG, et al. Worm proteins of Schistosoma mansoni reduce the severity of experimental chronic colitis in mice by suppressing colonic proinflammatory immune responses. PLoS ONE [Electronic Resource]. 2014;9:e110002.

    Article  PubMed  Google Scholar 

  38. Ruyssers NE, De Winter BY, De Man JG, Loukas A, Pearson MS, Weinstock JV, et al. Therapeutic potential of Helminth Soluble Proteins in TNBS-induced colitis in mice. Inflamm Bowel Dis. 2009;15:491–500.

    Article  PubMed  Google Scholar 

  39. Wangchuk P, Shepherd C, Constantinoiu C, Ryan RYM, Kouremenos KA, Becker L, et al. Hookworm-derived metabolites suppress Pathology in a mouse model of colitis and inhibit secretion of Key Inflammatory cytokines in Primary Human leukocytes. Infect Immun. 2019;87:4.

    Article  Google Scholar 

  40. Smallwood TB, Navarro S, Cristofori-Armstrong B, Watkins TS, Tungatt K, Ryan RYM, et al. Synthetic hookworm-derived peptides are potent modulators of primary human immune cell function that protect against experimental colitis in vivo. J Biol Chem. 2021;297:100834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ferreira I, Smyth D, Gaze S, Aziz A, Giacomin P, Ruyssers N, et al. Hookworm excretory/secretory products induce interleukin-4 (il-4)+ il-10+ cd4+ t cell responses and suppress pathology in a mouse model of colitis. Infect Immun. 2013;81(6):2104–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cancado GGL, Fiuza JA, de Paiva NCN, Lemos LDD, Ricci ND, Gazzinelli-Guimaraes PH, et al. Hookworm products ameliorate Dextran Sodium Sulfate-induced colitis in BALB/c mice. Inflamm Bowel Dis. 2011;17:2275–86.

    Article  PubMed  Google Scholar 

  43. Loukas A, Prociv P. Immune responses in hookworm infections. Clin Microbiol Rev. 2001;14.

  44. Riganò R, Buttari B, Profumo E, Ortona E, Delunardo F, Margutti P, et al. Echinococcus Granulosus Antigen B impairs human dendritic cell differentiation and polarizes immature dendritic cell maturation towards a Th2 cell response. Infect Immun. 2007;75:1667–78.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Kawai T, Akira S. TLR signaling. Cell Death Differ. 2006;13:816–25.

    Article  CAS  PubMed  Google Scholar 

  46. Nono JK, Pletinckx K, Lutz MB, Brehm K. Excretory/secretory-products of Echinococcus multilocularis larvae induce apoptosis and tolerogenic properties in dendritic cells in vitro. PLoS Negl Trop Dis. 2012;6:e1516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Harn DA, McDonald J, Atochina O, Da’dara AA. Modulation of host immune responses by helminth glycans. Immunol Rev. 2009;230:247–57.

    Article  CAS  PubMed  Google Scholar 

  48. van Riet E, Everts B, Retra K, Phylipsen M, van Hellemond JJ, Tielens AGM, et al. Combined TLR2 and TLR4 ligation in the context of bacterial or helminth extracts in human monocyte derived dendritic cells: molecular correlates for Th1/Th2 polarization. BMC Immunol. 2009;10:9.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Cvetkovic J, Sofronic-Milosavljevic L, Ilic N, Gnjatovic M, Nagano I, Gruden-Movsesijan A. Immunomodulatory potential of particular Trichinella spiralis muscle larvae excretory-secretory components. Int J Parasitol. 2016;46:833–42.

    Article  CAS  PubMed  Google Scholar 

  50. Bai X, Wu X, Wang X, Guan Z, Gao F, Yu J, et al. Regulation of cytokine expression in murine macrophages stimulated by excretory/secretory products from Trichinella spiralis in vitro. Mol Cell Biochem. 2012;360:79–88.

    Article  CAS  PubMed  Google Scholar 

  51. Donnelly S, O’Neill SM, Stack CM, Robinson MW, Turnbull L, Whitchurch C, et al. Helminth cysteine proteases inhibit TRIF-dependent activation of macrophages via degradation of TLR3. J Biol Chem. 2010;285:3383–92.

    Article  CAS  PubMed  Google Scholar 

  52. Everts B, Hussaarts L, Driessen NN, Meevissen MHJ, van der Schramm G, et al. Schistosome-derived omega-1 drives Th2 polarization by suppressing protein synthesis following internalization by the mannose receptor. J Exp Med. 2012;209:1753–67. S1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schierack P, Lucius R, Sonnenburg B, Schilling K, Hartmann S. Parasite-specific immunomodulatory functions of filarial cystatin. Infect Immun. 2003;71:2422–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Donahue PE, Samelson S, Nyhus LM, Bombeck CT. The floppy Nissen fundoplication. Effective long-term control of pathologic reflux. Arch Surg. 1985;120:663–8.

    Article  CAS  PubMed  Google Scholar 

  55. Cooper D, Eleftherianos I. Parasitic nematode immunomodulatory strategies: recent advances and perspectives. Pathogens. 2016;5:58.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Hartmann S, Lucius R. Modulation of host immune responses by nematode cystatins. Int J Parasitol. 2003;33:1291–302.

    Article  CAS  PubMed  Google Scholar 

  57. Manoury B, Gregory WF, Maizels RM, Watts C. Bm-CPI-2, a cystatin homolog secreted by the filarial parasite Brugia Malayi, inhibits class II MHC-restricted antigen processing. Curr Biol. 2001;11:447–51.

    Article  CAS  PubMed  Google Scholar 

  58. Ziegler T, Rausch S, Steinfelder S, Klotz C, Hepworth MR, Kühl AA, et al. A Novel Regulatory Macrophage Induced by a Helminth Molecule instructs IL-10 in CD4 + T cells and protects against mucosal inflammation. J Immunol. 2015;194:1555–64.

    Article  CAS  PubMed  Google Scholar 

  59. Xu N, Bai X, Liu Y, Yang Y, Tang B, Shi HN, et al. The anti-inflammatory Immune response in early trichinella spiralis intestinal infection depends on serine protease inhibitor-mediated alternative activation of macrophages. J Immunol. 2021;206:963–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Liu W, Liu J, Wu J, Zhang L, Liu F, Yin L, et al. Novel mechanism of inhibition of dendritic cells maturation by mesenchymal stem cells via Interleukin-10 and the JAK1/STAT3 signaling pathway. PLoS ONE. 2013;8:e55487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hosken NA, Shibuya K, Heath AW, Murphy KM, O’Garra A. The effect of antigen dose on CD4 + T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model. J Exp Med. 1995;182:1579–84.

    Article  CAS  PubMed  Google Scholar 

  62. Johnston CJC, Smyth DJ, Dresser DW, Maizels RM. TGF-β in tolerance, development and regulation of immunity. Cell Immunol. 2016;299:14–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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This work was supported by Institutional Fund Projects under grant no (IFPRC-408160-290-2020). Therefore, the authors gratefully acknowledge technical and financial support from the Ministry of Education and King Abdulaziz University, Jeddah, Saudi Arabia.

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Conception and design: T.T., M.A., F.M., A.Z. Acquisition of the data: A.N. and H.A. perform the search strategy for possible keywords that belong to the aim of this project. Analysis and interpretation of the data: the selected papers were screened by T.T., M.A., A.Z., A.A., and F.M.; the study’s title and abstract independently to see if it meets the inclusion/exclusion criteria. Following that, researchers MA, AZ, TT, and FM independently conducted a two-step full-text literature search to determine eligibility further. Drafting and revising the paper: T.T., A.Z., M.A., I.S., R.A.,A.A., and S.A. Supervision and final revision: F.M., A.H. All authors contributed to the article and approved the submitted version.

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Alghanmi, M., Minshawi, F., Altorki, T.A. et al. Helminth-derived proteins as immune system regulators: a systematic review of their promise in alleviating colitis. BMC Immunol 25, 21 (2024).

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